LV10388B - Ophthalmic compositions comprising combinations of a carbonic anhydrase inhibitor and a -adrenergic antagonist - Google Patents

Abstract

The combination of β-adrenergic antagonist and local carbonic anhydrase inhibitor is particularly suitable for the increased eye pressure treatment, especially for those patients who only suffer an insufficient response to treatment with β-adrenergic antagonists.

Description

5 LV 10388 -1-

TITLE OF THE INVENTION

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OPHTHALMIC COMPOSITIONS COMPRISING COMBINATIONS OF A CARBONIC ANHĪDRASE INHIBITOR AND A β-ADRENERGIC ANTAGONIST

ļs SUMMARY OF THE INVENTION

This invention relates to novel ophthalmic compositions comprising a topical carbonic anhydrase inhibitor of structure: 20

Z

25 uherein A, Z, R1 and X are as hereinafter defined, or 30 -2- an ophthamologically acceptable salt thereof and a β-adrenergic antagonist selected from betaxolol, bufenolol, carteolol, levobunolol, metipranolol, and timolol, or an ophthalmologically acceptable salt thereof.

The invention is also concerned with the use of the novel ophthalmic compositions in the treatment of ocular hypertension.

More particularly, it relates to such ophthalmic combinations and their use in the treatment of ocular hypertension and glaucoma, wherein the β-adrenergic antagonist is l-Ctert-butylamino)-3-C(4-morpholino-l,2,5-thiadiazol-3-yl)oxy]-2-propanol, or an ophthalmologically acceptable salt thereof which name includes the (S)-(-)- and (R)-(+)~ enantiomers and any mixtures thereof, including racemic material. The (S)-(-)-enantiomer is generally known as timolol.

BACKGROUND OF THE INVENTION

Glaucoma is a degenerative disease of the eye wherein the intraocular pressure is too high to permit normai eye function. As a result, damage may occur to the optic nerve head and result in irreversible loss of visual function. If untreated, glaucoma may eventually lead to blindness. Ocular hypertension, i.e., the condition of elevated intraocular pressure without optic nerve head damage or characteristic glaucomatous visual field defects, is now believed by the majority of ophthalmologists to represent merely the earliest phase in the onset of glaucoma. -3- -3- LV 10388

Many of the drugs formerly used to treat glaucoma proved not entirely satisfactory. The early methods of treatment of glaucoma employing pilocarpine produced undesirable local effects that made this drug, though valuable, unsatisfactory as a first line drug. More recently, clinicians have noted that many β-adrenergic antagonists are effective in reducing intraocular pressure. While many of these aģents are effective for this purpose, there exist some patients with whom this treatment is not effective or not sufficiently effective. Many of these aģents also have other characteristics, e.g., membrane stabilizing activity, that become more apparent with increased doses and render them unacceptable for chronic ocular use.

The β-adrenergic antagonist (S)-l-(tert-butylamino)-3-[(4-morpholino-l,2,5-thiadiazol-3-yl)-oxy]-2-propanol, timolol, was found to reduce intraocular pressure and to be devoid of many unwanted side effects associated with pilocarpine and, in addition, to possess advantages over many other β-adrenergic antagonists, e.g., to be devoid of local anesthetic properties, to have a long duration of activity, and to display minimal loss of effect with increased duration of dosing.

Although pilocarpine and β-adrenergic antagonists reduce intraocular pressure, none of these drugs manifests its action by inhibiting the enzyme carbonic anhydrase, and thus they do not take advantage of reducing the contribution to agueous humor formation made by the carbonic anhydrase pathway. 5 -4- 5 -4- * Ιθ 15 2θ 25 Aģents referred to as carbonic anhydrase inhibitors block or impede this inflow pathway by inhibiting the enzyme carbonic anhydrase. While such carbonic anhydrase inhibitors are now used to treat intraocular pressure by systemic routes, they thereby have the distinct disadvantage of inhibiting carbonic anhydrase throughout the entire body. Such a gross disruption of a basie enzyme system is justified only during an acute attack of alarmingly elevated intraocular pressure, or when no other aģent is effective.

For several years,the desirability of directing the carbonic anhydrase inhibitor to only the desired ocular target tissue has been recognized. Because carbonic anhydrase inhibitors have a profound effect in altering basie physiological processes, the avoidance of a systemic route of administation serves to diminish, if not entirely eliminate, those side effects caused by inhibition of carbonic anhydrase such as metabolic acidosis, vomiting, numbness, tingling, general malaise and the like. Topically effective carbonic anhydrase inhibitors are disclosed in U.S. Patent Nos. 4,386,098; 4,416,890; 4,426,388; 4,668,697; and 4,863,922 and PCT Publication W0 91/15486. As yet, no topically effective carbonic anhydrase inhibitors are generally available for clinical use.

Thus, when a carbonic anhydrase inhibitor is combined with a β-adrenergic antagonist, there is experienced an effect that reduces the intraocular pressure below that obtained by either medicament individually. 30 -5- -5-LV 10388

The activity of carbonic anhydrase inhibitors currently under development wanes 6 to 8 hours post-dose, meaning that as single aģents these carbonic anhydrase inhibitors must be administered at least three times a day to maintain the desired lovering of intraocular pressure. The combination of this invention maintains the desired lowering of intraocular pressure for a full twelve hours.

Because of this increased duration of action, the combination disclosed herein is effective when administered only twice a day. Patient compliance is anticipated to be greater with twice a day administration than with three times a day administration.

The use of oral carbonic anhydrase inhibitors in combination with the topical β-adrenergic antagonist timolol and the resulting multiplicity of their effects is disclosed in Berson et al., American Journal of Ophthalmologv 1981, 12., 788-791. However, the combination of an oral carbonic anhydrase inhibitor with a topical β-adrenergic antagonist presents two disadvantages. The first disadvantage is that the systemic use of a carbonic anhydrase inhibitor inhibits carbonic anhydrase throughout the body and exerts the same profound negative effects on basie metabolism whether it is used alone or in combination with a topical β-adrenergic antagonist. Secondly, there is poor patient compliance with simultaneous administration of both an oral and topical medicament.

The combination disclosed herein is effective either by co-administration of the 6- medicaments in one solution or as a combined therapy achieved by prior administration. of either the carbonic anhydrase inhibitor or the B-adrenergic antagonist folloved by administration of the other solution. The use of a single solution containing both active medicaments is preferred.

The combination of this invention is suggested in U.S. Patent No. 4,863,922, but a precise formulation of the relative combination of medicaments to give effective reduction of intraocular pressure is neither taught nor disclosed therein.

There exists a patient population insufficiently responsive to available B-adrenergic antagonists who will benefit from the combination disclosed herein. Because of the combined effect of the β-adrenergic antagonist and the carbonic anhydrase inhibitor, these othervise refractory patients can obtain a marked beneficial reduction in intraocular pressure from such a combination.

Furthermore, there exists a patient population who will benefit from a combination where the minimal dosage of one or both of the medicaments is employed, thus minimizing the possibility of the occurrence of undesirable effects of one or both of the medicaments which would be more likely to become apparent with chronic use at the higher dosage.

DĒTAILED DESCRIPTION OF THE INVENTION

The novel ophthalmic compositions of this invention comprise a therapeutically effective amount of a topical carbonic anhydrase inhibitor and a -7- -7- LV 10388 β-adrenergic antagonist. The topical carbonic anhydrase inhibitor of the novel composition has the structural formula:

or an ophthalmologically acceptable salt thereof wherein: A is carbon or nitrogen, preferably carbon; Z is -NHR or -OR; R is Cļ_6 alkyl, either straight or branched chain, preferably C2_4 alkyl such as ethyl, propyl or isobutyl; R1 is (a) hydrogen, (b) Cļ_3 alkyl, preferably methyl, ethyl or n-propyl, or (c) Cļ_4 alkoxy-Cļ_4 alkyl, preferably methoxypropyl; and X is -SO2- or -C(0)-.

The carbon atoms to which Z and R*· are bonded may be chiral. When named according to absolute config-uration, e.g., (R,S) or (S,S), the first letter represents the chirality the carbon atom to which Z is bonded and the second letter represents the charality of A when A is carbon. The carbonic anhydrase inhibitors of this invention accordingly may be used as diastereomeric mixtures or single enantiomers or as racemic mixtures. 5 -8- 5 -8- * 10 15 20 25

The β-adrenergic antagonist of the novel composition is selected from betaxolol, bufenolol, carteolol, levobunolol, metipranolol, and timolol, or an ophthalmologically acceptable salt thereof.

Most of the β-adrenergic antagonists and carbonic anhydrase inhibitors recited above have at least one asymmetric carbon atom and accordingly may exist as diastereomers or (+)- or (-)-enantiomers. This invention contemplates the use of any of the diastereomers or enantiomers or mixtures thereof including racemic forms.

The preferred β-adrenergic antagonist for use in the novel composition of this invention is timolol as its maleate salt.

The novel ophthalmic formulations of this invention comprise about 0.05 to 57. (w/w) of carbonic anhydrase inhibitor, usually about 0.5 to 37. (w/w) and about 0.01 to 17. (w/w) of β-adrenergic antagonist, preferably about 0.1 to 0.57. (w/w) to be administered on a 1 to 2 times a day schedule.

The novel method of this invention comprises the topical ocular administration of about 0.025 to 5 mg per day, preferably about 0.25 to 3 mg per,.day, of carbonic anhydrase inhibitor and concomitant, prior, or previous administration of about 0.005 to 1 mg per day, preferably about 0.05 to 0.5 mg per day, of β-adrenergic antagonist to each eye.

As a unit dosage, between 0.025 and 2.5 mg of the carbonic anhydrase inhibitor and 0.005 to 0.5 mg of the β-adrenergic antagonist are applied to the eye; preferably, 0.25 to 1.5 mg of the carbonic anhydrase inhibitor and 0.05 to 0.25 mg of the β-adrenergic antagonist. 30

Suitable subjects for the administration of the formulation of the present invention include primates, man and other animals, particularly man and domesticated animals such as cats and dogs.

For topical ocular administration the novel formulations of this invention may take the form of Solutions, gels, ointments, suspensions or solid inserts, formulated so that a unit dosage comprises a therapeutically effective amount of each active component or some submultiple thereof.

Typical ophthalmologically acceptable carriers for the novel formulations are, for example, water, mixtures of water and water-miscible solvents such as lower alkanols or aralkanols, vegetable oils, polyalkylene glycols, petroleum based jelly, ethyl cellulose, ethyl oleate, carboxymethylcellulose, polyvinylpyrrolidone, isopropyl myristate and other conventionally employed acceptable carriers. The pharmaceutical preparation may also contain non-toxic auxiliary substances such as emulsifying, preserving, wetting aģents, bodying aģents and the like, as for example, polyethylene glycols 200, 300, 400 and 600, carbotfaxes 1,000, 1,500, 4,000, 6,000 and 10,000, antibacterial components such as quaternary ammonium compounds, phenylmercuric salts known to have cold sterilizing properties and which are non-injurious in use, thimerosal, benzalkonium chloride, methyl and propyl paraben, benzyldodecinium bromide, benzyl alcohol, phenylethanol, buffering ingredients such as sodium chloride, sodium borate, sodium acetate, or gluconate buffers, and other -10- conventional ingredients such as sorbitan mono-laurate, triethanolamine, polyoxyethylene sorbitan monopalmitylate, dioctyl sodium sulfosuccinate, monothioglycerol, thiosorbitol, ethylenediamine tetra-acetic acid, and the like. Additionally, suitable ophthalmic vehicles can be used as carrier media for the present purpose including conventional phosphate buffer vehicle systems, isotonic boric acid vehicles, isotonic sodium chloride vehicles, isotonic sodium borate vehicles and the like.

The formulation may also include a gum such as gellan gum at a concentration of 0.1% to 2% by weight so that the aqueous eyedrops gel on contact with the eye, thus providing the advantages of a solid ophthalmic insert as described in U.S. Patent 4,861,760.

The pharmaceutical preparation may also be in the form of a solid insert such as one which after dispensing the drug remains essentially intact as described in U.S. Patents 4,256,108; 4,160,452; and 4,265,874; or a bio-erodible insert that either is soluble in lacrimal fluīds, or otherwise disintegrates as described in U.S. Patent 4,287,175 or EP0 publication 0,077,261. -11-LV 10388

The following examples of ophthalmic formulations are given by way of illustration. EXAMPLE 1 SOT.UTTON HOMPOSITION I (S,S)-(-)-5,6-dihydro-4-ethyl-amino-6-methyl-4H-thieno-[2,3b]thiopyran-2-sulfonamide-7,7-dioxide monohydrochloride 22.26 g

II IU 10 22.26 g 1.113 g (S)-(-)-1-(tert-butvlamino)- 3-[(4-morpholino-l,2,5- thiadiazol-3-yl)oxy]-2- 15 propanoi maleate 6.834 g 1.367 g 6.834 g Sodiiun citrate.2H20 2.940 g 2.940 g 2.940 g 20 Benzalkonium Chloride 0.075 g 0.075 g 0.075 g Hydroxyethylcellulose 5.00 g 5.00 g 5.00 g Sodium hydroxide q.s. pH = 6.0 pH = 6.0 pH = 6.0 25 Mannitol 16.00 g 21.00 g 35.90 g Water for injection q.s. ad. 1000 g 1000 g 1000 g 30 -12-

The active compounds, sodium citrate benzalkonium chloride (in a 507. W/W solution), and mannitol are dissolved in approximately 400 mL water for injection in a tared and sterile vessel. The pH of the composition is adjusted to 6.0 by addition of 0.2 N sodium hydroxide solution, and water for injection is added until the weight of composition equals 750 g. The composition is sterilized by filtration, pushing the solution with a 2 bar pressure of 0.45 micron filtrated nitrogen. Then 250 g of a 27. hydroxyethylcellulose autoclaved solution is added and the obtained solution is homogenized by stirring with a magnetic stirring bar. The solution is aseptically subdivided into 3.5 mL aliquots and sealed. EXAMPLE 2 SOLUTION OOMPOSITION (S,S)-(-)-5,6-dihydro-4-ethyl-amino-6-methyl-4H-thieno-[2,3b]thiopyran-2-sulfonamide-7,7-dioxide .

I

II

III 1.0 mg 1.5 mg 0.5 mg 4-[2-hydroxy-3-(l-methylethyl)-amino]-propoxy]-2,3,6- trimethylphenol-l-acetate 0.3 mg 0.2 mg 0.4 mg

Quantity sufficient to give final pH 5.5 - 6.0

Monobasic sodium phosphate 2H20

Dibasic sodium phosphate •12H20 -13- -13- LV 10388

Benzalkonium chloride 0.10 mg 0.10 mg 0.10 mg Polysorbate 80 0.2 mg 0.2 mg 0.2 mg Water for injection q.s. ad. 1.0 mL 1.0 mL 1.0 mL

The active compounds, phosphate buffer salts, benzalkonium chloride, and Polysorbate 80 are added to and suspended or dissolved in water. The pH of the composition is adjusted to 5.5-6.0 and diluted to volume. The composition is rendered sterile by filtration through a sterilizing filter. EXAMPLE 3

SOLUTION COMPOSITION I H trans-5,6-dihydro-4-ethylamino-6-methyl-4H-thieno[2,3b]thiopyran-

2-sulfonamide-7,7-dioxide 1.7 mg 0.8 mg 1-[4-[2-(cyclopropylmethoxy)-ethyl]phenoxy]-3-(l-methylethyl)-amino]-2-propanol 0.3 mg 0.2 mg Monobasic sodium phosphate.2H20 9.5 mg 9.5 mg Dibasic sodium phosphate.12Η20 28.5 mg 28.5 mg Benzalkonium chloride 0.10 mg 0.10 mg Sodium hydroxide q.s. pH 6.0 pH 6.0 Water for injection q.s. ad. 1.0 mL 1.0 mL -14-

The active compounds, phosphate buffer salts, and benzalkonium chloride are added to and dissolved in water. The pH of the composition is adjusted to 6.0 with sodium hydroxide and the final solution is diluted to volume. The solution is rendered sterile by filtration through a sterilizing filter. EXAMPLE 4

SOLUTION COMPOSITION I II III (S,S)-(-)-5,6-dihydro-4-propyl-amino-6-me thoxypropyl-4H-thieno-[2,3b]thiopyran-2-sulfonamide- 7,7-dioxide monohydrochloride 21.0 g 21.0 g 1-5 g (S)-(-)-1-(tert-butvlamino)-3-[(4-roo rpho1ino-1,2,5-thiadiazol-3-yl)oxy]-2-propanol maleate 6.8 g 1-3 g 6.8 g Sodium citrate.2H20 2.9 g 2.9 g 2.9 g Benzalkonium Chloride 0.075 g 0.075 g 0.075 g Hydroxyethylcellulose 5.0 g 5.0 g 5.0 g Sodium hydroxide q.s. pH = 6.0 pH « 6.0 pH = 6.0 Mannitol 35.9 g 35.9 g 35.9 g Water for injection q.s. ad. 1000 g 1000 g 1000 g -15-

The active compounds, sodium citrate, benzalkonium chloride (in a 50% W/W solution), and mannitol are dissolved in approximately 400 mL water for injection in a tared and sterile vessel. The pH of the composition is adjusted to 6.0 by addition of 0.2 N sodium hydroxide solution and water for injection is added until the weight of composition eguals 750 g. The composition is sterilized by filtration, pushing the solution with a 2 bar pressure of 0.45 micron filtrated nitrogen. Then 250 g of a 27o hydroxyethylcellulose autoclaved solution is added and the obtained solution is homogenized by stirring with a magnetic stirring bar. The solution is aseptically subdivided into 3.5 mL aliquots and sealed. EXAMPLE 5 20 LV 10388

SOLUTION COMPOSITION I Π IH (S,S)-(-)-5,6-dihydro-4-propylamino-6-nie thoxypropyl-4H- thieno [2,3b] thiopyran-2-sulfonamide-7,7- dioxide 1.0 mg 1.5 mg 0.5 mg 4-[2-hydroxy-3-(1-me thylethyl)-amino]propoxy]-2,3,6- trimethylphenol-l-acetate 0.3 mg 0.2 mg 0.4 mg 30 -16-

Monobasic sodium phosphate .2H20

Dibasic sodium phosphate .12H20

Benzalkonium chloride Polysorbate 80

Water for injection q.s. ad.

Quantity sufficient to give final pH 5.5 - 6.0

0.10 mg 0.10 mg 0.10 mg 0.2 mg 0.2 mg 0.2 mg 1.0 mL 1.0 mL 1.0 mL

The active compounds, phosphate buffer salts, benzalkonium chloride, and Polysorbate 80 are added to and suspended or dissolved in water. The pH of the composition is adjusted to 5.5-6.0 and diluted to volume. The composition is rendered sterile by filtration through a sterilizing filter. EXAMPLE 6

SOLIJTION COMPOSITION I II trans-5,6-dihydro-4-propylamino-6-methoxypropyl-4H-thieno[2,3b] thiopyran-2-sulfonamide-7,7- dioxide 1.7 mg 0.8 mg 1- [4-[2-(cyclopropylmethoxy)ethyl]-phenoxy]-3-(l-methylethyl)amino]- 2- propanol 0.3 mg 0.2 mg

Monobasic sodium phosphate.2H2O 9.5 mg 9.5 mg LV 10388

28.5 mg 0.10 mģ pH 6.0 1.0 mL

28.5 mg 0.10 mg pH 6.0 1.0 mL

Dibasic sodiura phosphate.I2H2O Benzalkonium chloride Sodium hydroxide q.s.

Water for injection q.s. ad.

The active compounds, phosphate buffer salts, and benzalkonium chloride are added to and dissolved in water. The pH of the composition is adjusted to 6.0 with sodium hydroxide and the final solution is diluted to volume. The solution is rendered sterile by filtration through a sterilizing filter. EXAMPLE 7

SOLUTION COMPOSITION I II III (S)-(+)-5,6-dihydro-A-isobutyl- amino-AH-thieno[2,3b]thiopyran- 2- sulfonamide-7,7-dioxide mono- hydrochloride 21.0 g 21.0 g 1.5 g (S)-(-)-!-(tert-butvlamino)- 3- [ (4-tnorpholino-l ,2,5-thiadiazol-3-yl)oxy]-2- propanol maleate 6.8 g 1.3 g 6.8 g -18-

Sodium citrate.21^0 2.9 g 2.9 g 2.9 g Benzalkonium Chloride 0.075 g 0.075 g 0.075 g Hydroxyethylcellulose 5.0 g 5.0 g 5.0 g Sodium hydroxide q.s. pH > 6.0 pH = 6.0 pH = 6.0 Mannitol 35.9 g 35.9 g 35.9 g Water for injection q.s. ad. 1000 g 1000 g 1000 g

The active compounds, sodium citrate, benzalkonium chloride (in a 507o W/W solution), and mannitol are dissolved in approximately 400 mL water for injection in a tared and sterile vessel. The pH of the composition is adjusted to 6.0 by addition of 0.2 N sodium hydroxide solution and water for injection is added until the weight of composition equals 750 g. The composition is sterilized by filtration, pushing the solution with a 2 bar pressure of 0.45 micron filtrated nitrogen. Then 250 g of a 27o hydroxyethylcellulose autoclaved solution is added and the obtained solution is homogenized by stirring with a magnetic stirring bar. The solution is aseptically subdivided into 3.5 mL aliquots and sealed. -19- -19-LV 10388 EXAMPLE 8

SOLUTION COMPOSITION (S)-(+)-5,6-dihydro-4-isobutyl- amino-4H-thieno[2,3b]thiopyran- I II III 2-sulfonamide-7,7-dioxide 1.0 mg 1.5 mg 0.5 mg 4-[2-hydroxy-3-(1-methylethyl)-amino]propoxy]—2,3,6— trimethylphenol-l-acetate 0.3 mg 0.2 mg 0,4 mg Monobasic sodium phosphate Quantity sufficient .2H20 to give Dibasic sodium phosphate .12H20 final pH 5.5 - 6.0 h Benzalkonium chloride 0.10 mg 0.10 mg 0.10 mg Polysorbate 80 0.2 mg 0.2 mg 0.2 mg Water for injection q.s. ad. 1.0 mL 1.0 mL 1.0 mL

The active compounds, phosphate buffer 25 salts, benzalkonium chloride, and Polysorbate 80 are added to and suspended or dissolved in water. The pH of the composition is adjusted to 5.5-6.0 and diluted to volume. The composition is rendered sterile by filtration through a sterilizing filter. 30 -20- EXAMPLE 9

SOLUTION COMPOSITION I II (S)-(+)-5,6-dihydro-4-isobutyl- amino-4H-thieno[2,3b]thiopyran- 2-sulfonamide-7,7-dioxide 1.7 mg 0.8 mg l-[4-[2-(cyclopropylmethoxy)- ethyl]-phenoxy]-3-(l-methylethyl) - amino]-2-propanol 0.3 mg 0.2 mg Monobasic sodium phosphate.2H2O 9.5 mg 9.5 mg Dibasic sodium phosphate.I2H2O 28.5 mg 28.5 mg Benzalkonium chloride 0.10 mg. 0.10 mg Sodium hydroxide q.s. pH 6.0 pH 6.0 Water for injection q.s. ad. 1.0 mL 1.0 mL

The active compounds, phosphate buffer salts, and.benzalkonium chloride are added to and dissolved in water. The pH of the composition is adjusted to 6.0 with sodium hydroxide and the final solution is diluted to volume. The solution is rendered sterile by filtration through a sterilizing filter. -21- LV 10388 EXAMPLE 10

SOLTJTION COMPOSITION I II

2.0 mg 0.2 mg 0.5 mg 0.5 mg 6.0 mg 6.0 mg Quantity sufficient to give final pH 5.5 - 6.0 0.10 mg 0.10 mg 0.2 mg 0.2 mg 1.0 mL 1.0 mL (S,S)-(-)-5,6-dihydro-4-ethyl-amino-6-methyl-4H-thieno[2,3b]-thiopyran-2-sulfonamide-7,7-dioxide monohydrochloride (Stert-butylamino)-3-[(4-morpholino-l,2,5-thiadiazol-3-yl)oxy]-2-propanol maleate GELRITE™ gellan gum

Monobasic sodium phosphate • 2H20

Dibasic sodium phosphate .12H20

Benzyldodecinium bromide

Polysorbate. 80

Water for injection q.s. ad.

The active compounds, GELRITE™ gellan gum, phosphate buffer salts, benzyldodecinium bromide and Polysorbate 80 are added to and suspended or dissolved in water. The pH of the composition is adjusted to 5.5-6.0 and diluted to volume. The composition is rendered sterile by ionizing radiation. -22- ΕΧΑΜΡΙιΕ 11

SOLUTION COMPOSITION I II (S)-( + )-5,6-dihydro-4-isobUtyl-amino-4H-thieno[2,3b]thiopyran- 3.0 mg 0.5 mg 0.5 mg 0.5 mg 6.0 mg 6.0 mg Quantity sufficient to give final pH 5.0 - 6.0 0.10 mg 0.10 mg 0.2 mg 0.2 mg 1.0 mL 1.0 mL I· 2- sulfonamide-7,7-dioxide (S)-(-)-l-(£fLr£-butylamino)- 3- [(4-morpholino-l,2,5-thiadiazol-3-yl)oxy]-2-propanol maleate GELRITE™ gellan gum

Monobasic sodium phosphate •2H20

Dibasic sodium phosphate .12H20

Benzyldodecinium bromide

Polysorbate 80

Water for injection q.s. ad.

The active compounds, GELRITE"1 gellan gum, phosphate buffer salts, benzyldodecinium bromide and Polysorbate 80 are added to and suspended or dissolved in water. The pH of the composition is adjusted to 5.0-6.0 and diluted to volume. The composition is rendered sterile by ionizing radiation. -23- LV 10388 EXAMPLE 12

SOLUTION COMPOSITION I II 5 (S,S)-(-)-5,6-dihydro-4-propyl-amino-6-methoxypropyl-4H-thieno[2,3b]thiopyran-2- sulfonamide-7,7-dioxide 2.0 mg 0.2 mg 10 (S)-(-)-l-(lLexJi-butylamino)-3-[(4-morpholino-l,2,5-thiadiazol-3-yl)oxy]-2- propanol maleate 0.5 mg 0.5 mg GELRITE™ gellan gum 6.0 mg 6.0 mg 15 20 25

Monobasic sodium phosphate . 2H20 Dibasic sodium phosphate .12HZ0 Benzyldodecinium bromide Polysorbate 80 Water for injection q.s. ad.

Quantity sufficient to give final pH 5.5 - 6.0 0.10 mg 0.10 mg 0.2 mg 0.2 mg 1.0 mL 1.0 mL

The active compounds, GELRITE™ gellan gum, phosphate buffer salts, benzyldodecinium bromide and Polysorbate 80 are added to and suspended or 30 dissolved in water. The pH of the composition is adjusted to 5.5-6.0 and diluted to volurae. The composition is rendered sterile by ionizing radiation. -24- EXAMPLE 13 SOLUTION COMPOSITION χ χχ (R)-(-)-5,6-dihydro-4-iso-butylamino-4H-thieno[2,3b]-thio-pyran-2-sulfonamide-7,7-dioxide 2.0 mg 0.5 mg 0.5 mg 0.5 mg 6.0 mg 6.0 mg 4-[2-hydroxy-3-(l-methylethyl)-amino]propoxy]-2,3,6-trimethylphenol-l-acetate GELRITE™ gellan gum

Quantity sufficient to give final pH 5.5 - 6.0 0.10 mg 0.10 mg 0.2 mg 0.2 mg

1.0 mL 1.0 nL

Monobasic sodium phosphate . 2H20

Dibasic sodium phosphate .12H20

Benzyldodecinium bromide 20

Polysorbate 80

Water for injection q.s. ad. 25 The active compounds, GELRITE’" gellan gum, phosphate buffer salts, benzyldodecinium bromide and Polysorbate 80 are added to and suspended or dissolved in water. The pH of the composition is adjusted to 5.5-6.0 and diluted to volume. The 30 composition is rendered sterile by ionizing radiation. -25- LV 10388 EXAMPLE 14

SOLUTION COHPOSITION X U cis-5,6-dihydro-4-ethylamino-6-methyl-4H-thi eno[2,3b]thiopyran-2-sulfonamide-7,7-dioxide monohydrochloride 2.0 mg 0.2 mg 4-[2-hydroxy-3-(l-methylethyl>-amino]propoxy]-2,3,6- trimethylphenol-l-acetate 0.5 mg 0.5 mg GELRITE™ gellan gum 6.0 mg 6.0 mg

Quantity sufficient to give final pH 5.5 - 6.0 0.10 mg 0.10 mg

Monobasic sodium phosphate .2H20

Dibasic sodium phosphate .12H20

Benzyldodecinium bromide

Polysorbate 80 0.2 mg 0.2 mg

Water for injection q.s. ad. 1.0 mL 1.0 mL

The active compounds, GELRITE™ gellan gum, phosphate buffer salts, benzyldodecinium bromide and Polysorbate 80 are added to and suspended or dissolved in water. The pH of the composition is adjusted to 5.5-6.0 and diluted to volume. The composition is rendered sterile by ionising radiation. -26- EXAMPLE 15

I II 2.0 mg 0.5 mg SOLUTION COMPOSITION cis-5,6-dihydro-4-propyl-amino-6-methoxypropyl-4H-thieno[2,3b]thiopyran-2-sulfonamide-7,7-dioxide 4-[2-hydroxy-3-(l-methylethyl)-amino]propoxy]-2,3,6- trimethylphenol-l-acetate 0.5 mg 0.5 mg GELRITE™ gellan gum 6.0 mg 6.0 mg

Monobasic sodium phosphate .2H20 Dibasic sodium phosphate .12H20 ,Benzyldodecinium bromide Polysorbate 80 Water for injection q.s. ad.

Quantity sufficient to give final pH 5.5 - 6.0 0.10 mg 0.10 mg

0.2 mg 0.2 mg 1.0 mL 1.0 iL

The active compounds, GELRITE™ gellan gum, phosphate buffer salts, benzyldodecinium bromide and Polysorbate 80 are added to and suspended or dissolved in water. The pH of the composition is adjusted to 5.5-6.0 and diluted to volume. The composition is rendered sterile by ionizing radiation. 30 -27- LV 10388 EXAMPLE 16

SOLŪTION COMPOSITION I II 5,6-dihydro-4-ethylamino-6-methyI-4H-thieno[2,3b]thiopyran-2-sulfonamide-7,7-dioxide monohydrochloride 2.0 mg 0.2 mg 1- [4-[2-(cyclopropylmethoxy)ethyl]-phenoxy]-3-(l-methylethyl)amino]- 2- propanol 0.5 mg 0.5 mg 6.0 mg 6.0 mg Quantity sufficient to give final pH 5.5 - 6.0 GELRITE"1 gellan gum

Monobasic sodium phosphate .2H20

Dibasic sodium phosphate .12H20 20

Benzyldodecinium bromide 0.10 mg 0.10 mg

Polysorbate 80 0.2 mg 0.2 mg

Water for injection q.s. ad. 1.0 mL 1.0 mL 25

The active compounds, GELRITE™ gellan gum, phosphate buffer salts, benzyldodecinium bromide and Polysorbate 80 are added to and suspended or dissolved in water. The pH of the composition is adjusted to 5.5-6.0 and diluted to volume. The composition is rendered sterile by ionizing radiation. 30 -28- EXAMPLE 17 SOLUTION COMPOSITION I H" 5,6-dihydro-4-isobutylamino-4H-thieno[2,3b]thiopyran- 2-sulfonamide-7,7-dioxide 2.0 mg 0.5 mg 1- [4-[2-(cyclopropylmethoxy)ethyl]-phenoxy]-3-(l-methylethyl)amino]- 2- propanol 0.5 mg 0.5 mg 6.0 mg 6.0 mg

Quantity sufficient to give final pH 5.5 - 6.0 0.10 mg 0.10 mg 0.2 mg 0.2 mg GELRITE™ gellan gum

Monobasic sodium phosphate 15 .2H20

Dibasic sodium phosphate .12H20

Benzyldodecinium bromide 20

Polysorbate 80

Water for injection q.s. ad. 1.0 mL 1.0 mL 25 The active compounds, GELRITE™ gellan gum, phosphate buffer salts, benzyldodecinium bromide and Polysorbate 80 are added to and suspended or dissolved in water. The pH of the composition is adjusted to 5.5-6.0 and diluted to volume. The 30 composition is rendered sterile by ionizing radiation. -29- -29- LV 10388 EXAMPLE 18

S0LUTI0N COMPOSITION I II 5,6-dihydro-4-propylamino-6-methoxypropyl-4H-thieno[2,3b]thiopyran-2-

sulfonamide-7,7-dioxide 2.0 mg l-[4-[2-(cyclopropylmethoxy)ethyl]- 0.2 mg 10 phenoxy]-3-(l-methylethyl)amino]· 2-propanol 0.5 mg 0.5 mg GELRITE™ gellan gum 6.0 mg 6.0 mg 15 Monobašic sodium phosphate • 2H20 Quantity sufficient to give Dibasic sodium phosphate .12H2° final pH 5, ,5 - 6.0 20 Benzyldodecinium bromide 0.10 mg 0.10 mg Polysorbate 80 0.2 mg 0.2 mg Water for injection q.s. ad. 1.0 mL 1.0 mL 25

The active compounds, GELRITE™ gellan gum, phosphate buf.fer salts, benzyldodecinium bromide and Polysorbate 80 are added to and suspended or dissolved in water. The pH of the composition is 30 adjusted to 5.5-6.0 and diluted to volume. The composition is rendered sterile by ionizing radiation. -30- EXAMPLE 19 S9T.I/TTON OOMPOSITION I II III 5 3,4-Dihydro-4-me thoxy-2-me thy1-2H-thieno[3,2-e] -1,2-thiazine-6-sulfonamide-1,l-dioxide 22.26 g 22.26 g 1.113 g 10 (S)-(-)-l-(tert-butvlamino)-3-[ (4-morpholino-l,2,5-thiadiazol-3-yl)oxy]-2-propanol maleate 6.834 g 1.367 g 6.834 g 15 Sodiura citrate.2H20 2.940 g 2.940 g 2.940 g Benzalkonium Chloride 0.075 g 0.075 g 0.075 g 20 Hydroxyethylcellulose 5.00 g 5.00 g 5.00 g Sodium hydroxide q.s. pH = 6.0 pH = 6.0 pH = 6.0 Mannitol 16.00 g 21.00 g 35.90 g 25 Water for injection q.s. ad. 1000 g 1000 g 1000 g 30 LV 10388 -31- EXAMPLE 20 SOLUTION nOMPOSĪTION 3,4-Dihydro-4-e thylamino-2-methyl-2H-thieno[3,2-e]-l,2-thiazine-6-sulfonamide-1,1- I 11 III dioxide hydrochloride 22.26 g 22.26 g 1.113 g (S)-(-)-l-(tert-butvlamino)-3-[(4-morpholino-l,2,5-thiadiazol-3-yl)oxy]-2-propanol maleate 6.834 g 1.367 g 6.834 g Sodium citrate.2H20 2.940 g 2.940 g 2.940 g Benzalkonium Chloride 0.075 g 0.075 g 0.075 g Hydroxyethylcellulose 5.00 g 5.00 g 5.00 g Sodium hydroxide q.s. pH = 6.0 pH = 6.0 pH = 6.0 Mannitol 16.00 g 21.00 g 35.90 g Water for injection q.s. ad. 1000 g 1000 g 1000 g -32- EXAMPLE 21 SOT.UTION OOMPOSITION 1 II 111 3,4-Dihydro-2-methyl-4-(2-methyl)propylamino-2H-thieno-[3,2-e]-l,2-thiazine-6-sulfon- amide-1,l-dioxide hydrochloride 22.26 g 22.26 g 1.113 g (S)-(-)-l-(tert-butvlamino)-3-[(4-morpholino-l,2,5-thiadiazol-3-yl)oxy]-2-propanol maleate 6.834 g 1.367 g 6.834 g 1 · Sodium citrate.2H£0 2.940 g 2.940 g 2.940 g Benzalkonium Chloride 0.075 g 0.075 g 0.075 g Hydroxyethylcellulose 5.00 g 5.00 g 5.00 g Sodium hydroxide q.s. pH = 6.0 pH = 6.0 pH = 6.0 Mannitol 16.00 g 21.00 g 35.90 g Water for injection q.s. ad. 1000 g 1000 g 1000 g -33- -33-LV 10388 EXAMPLE 22

SOLUTION COMPOSITION I II III 5 R-(+)-3,4-Dihydro-4-ethylamino- 2-methyl)-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide-1,1- dioxide hydrochloride 22.26 g 22.26 g 1.113 g 10 (S)-(-)-l-(tĢrt-butylamino)-3-[(4-morpholino-l,2,5-thiadiazol-3-yl)oxy]-2-propanol maleate 6.834 g 1-367 g 6.834 g 15 Sodium citrate.2H20 2.940 g 2.940 g 2.940 g Benzalkonium Chloride 0.075 g 0.075 g 1. 0.075 g 20 Hydroxyethylcellulose 5.00 g 5.00 g 5.00 g Sodium hydroxide q.s. pH = 6.0 pH = 6.0 pH = 6.0 Mannitol 16.00 g 21.00 g 35.90 g 25 Water for injection q.s. ad. 1000 g 1000 g 1000 g 30

III -34- EXAMPLE 23

SOLUTION nOMPOSITION I II 5 R-(+)-3,4-Dihydro-4-ethylamino- 2- (2-methoxy)ethyl-2H-thieno- [3,2-e]-1,2-thiazine-6-sulfon- 1.113 g amide-l,l-dioxide hydrochloride 22.26 g 22.26 g (S)—(-)-1-(tert-butvlamino)- 3- [(4-morpholino-1,2,5-thiadiazol-3-yl)oxy]-2- propanol maleate 6.834 g 1.367 g 6.834 g 15 Sodium citrate.2H20 2.940 g 2.940 g 2.940 g Benzalkonium Chloride 0.075 g 0.075 g 0.075 g 20 Hydroxyethylcellulose 5.00 g 5.00 g 5.00 g Sodium hydroxide q.s. pH = 6.0 pH = 6.0 pH = 6.0 Mannitol 16.00 g 21.00 g 35.90 g 25 Water for injection q.s. ad. 1000 g 1000 g 1000 g 30 -35-LV 10388 EXAMPLE 24 SOLUTION COMPOSITĪON I II III R-(+)-3,4-Dihydro-2-(2-methoxy)· ethyl-4-propylamino-2H-thieno-[3,2-e]-l,2-thiazine-6-sulfon-amide-1, l-dioxide hydrochloride 22.26 g 22.26 g 1.113 g (S)-(-)-l-(tert-butvlainino)-3-[(4-morpholino-l,2,5-thiadiazol-3-yl)oxy]-2-propanol maleate 6.834 g 1.367 g 6.834 g Sodium citrate.2H20 2.940 g 2.940 g 2.940 g Benzalkonium Chloride 0.075 g 0.075 g 0.075 g Hydroxyethylcellulose 5.00 g 5.00 g 5.00 g Sodium hydroxide q.s. pH = 6.0 pH = 6.0 pH = 6.0 • Mannitol 16.00 g 21.00 g 35.90 g

Water for injection q.s. ad. 1000 g 1000 g 1000 g 5 -36- EXAMPLE 25

SOLUTION COMPOSITION I II 3,4-Dihydro-4-methoxy-2-methyl-2H-thieno[3,2-e]-l,2-thiazine- 6-sulfonamide-l,l-dioxide 2.0 mg 0.2 mg 10 (S)-(-)-1-(££r£-butylamino)-3-[(4-morpholino-1,2,5-thiadiazol-3-yl)oxy]-2- propanol maleate 0.5 mg 0.5 mg GELRITE™ gellan gum 6.0 mg 6.0 mg 15

Quantity sufficient to give final pH 5.5 - 6.0 0.10 mg 0.10 mg

0.2 mg 0.2 mg 1.0 mL 1.Ό mL

Monobasic sodium phosphate .2H20

Dibasic sodium phosphate .12H20 20

Benzyldodeciniura bromide

Polysorbate 80

Water for injection q.s. ad.

The active compounds, GELRITE™ gellan gum, phosphate buffer salts, benzyldodecinium bromide and Polysorbate 80 are added to and suspended or dissolved in 30 water. The pH of the composition is adjusted to 5.5-6.0 and diluted to volume. The composition is rendered sterile by ionizing radiation. -37- LV 10388 EXAMPLE 26 15 SOLUTION COMPOSITION 3,4-Dihydro-4-ethylamino-2-methyl-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide-l,l-dioxide hydrochloride ( S )-(-)·-1-( iL£li-butyl am i no ) -3-[(4-morpholino-l,2,5-thiadiazol-3-yl)oxy]-2-propanol maleate

I II 2.0 mg 0.2 mg 0.5 mg 0.5 mg GELRITE™ gellan gum 6.0 mg 6.0 mg

Quantity sufficient to give final pH 5.5 - 6.0 0.10 mg 0.10 mg

0.2 mg 0.2 mg 1.0 mL 1.Ό mL

Monobasic sodium phosphate ,2H20

Dibasic sodium phosphate 20 .12H20

Benzyldodecinium bromide

Polysorbate 80 25

Water for injection q.s. ad.

The active compounds, GELRITE"1 gellan gum, phosphate buffer salts, benzyldodecinium bromide and 30 Polysorbate 80 are added to and suspended or dissolved in water. The pH of the composition is adjusted to 5.5-6.0 and diluted to volume. The composition is rendered sterile by ionizing radiation. -38- EXAMPLE 27

SOLUTION COMPOSITION I II 3,4-Dihydro-2-methy-4-(2-methyl)propylamino-2H-thieno-[3,2-e]-l,2-thiazine-6-sulfon-amide-1,l-dioxide hydrochloride 2.0 mg 0.2 mg (S)-(-)-l-(£er£-butylamino)-3-[(4-morpholino-l,2,5-thiadiazol-3-yl)oxy]-2- propanol maleate 0.5 mg 0.5 mg GELRITE™ gellan gum 6.0 mg 6.0 mg

Quantity sufficient to give final pH 5.5 - 6.0 0.10 mg 0.10 mg

Monobasic sodium phosphate .2H20

Dibasic sodium phosphate .12H20

Benzyldodecinium bromide

Polysorbate 80 0.2 mg 0.2 mg

Water for injection q.s. ad. 1.0 mL 1.0 mL

The active compounds, GELRITE™ gellan gum, phosphate buffer salts, benzyldodecinium bromide and Polysorbate 80 are added to and suspended or dissolved in water. The pH of the composition is adjusted to 5.5-6.0 and diluted to volume. The composition is rendered sterile by ionizing radiation. -39- LV 10388 EXAMPLE 28

5 . SOLUTION COMPOSITION R-(+)-3,4-Dihydro-4-ethyl-amino-2-methyl-2H-thieno-[3,2-e]-l,2-thiazine-6-sulfon- I II 10 amide-1,l-dioxide hydrochloride ('S)-('-)-l-itert-butvlamino>-3-[(4-morpholino-l,2,5-thiadiazol-3-yl)oxy]-2- 2.0 mg 0.2 mg propanol maleate 0.5 mg 0.5 mg 15 GELRITE™ gellan gum 6.0 mg 6.0 mg Monobasic sodium phosphate .2H20 Quantity sufficient to give 20 Dibasic sodium phosphate .12H20 final pH 5 .5 - 6.0 Benzyldodecinium bromide 0.10 mg 0.10 mg 25 Polysorbate 80 0.2 mg 0.2 mg Water for injection q.s. ad. 1.0 mL 1.0 mL

The active compounds, GELRITE™ gellan gum, phosphate buffer salts, benzyldodecinium bromide and 30 Polysorbate 80 are added to and suspended or dissolved in water. The pH of the composition is adjusted to 5.5-6.0 and diluted to volume. The composition is rendered "sterile by ionizing radiation. EXAMPLE 29

SOLUTION COMPOSITION R-(+)-3,4-Dihydro-4-ethyl-amino-2-(2-methoxy)ethyl-2H-thieno[3,2-e]-l,2-thiazine-6-sulfonamide l,l-dioxide hydro- I II chloride 2.0 mg 0.2 mg (S)-(-)-l-(tert-butvlamino)-3-[(4-morpholino-l,2,5-thiadiazol-3-yl)oxy]-2-propanol maleate 0.5 mg 0.5 mg GELRITE™ gellan gum 6.0 mg 6.0 mg Monobasic sodium phosphate • 2H20 Dibasic sodium phosphate .12H20 Quantity sufficient to give final pH 5.5 - 6.0 Benzyldodecinium bromide • 0.10 mg 0.10 mg Polysorbate 80 0.2 mg 0.2 mg Water for injection q.s. ad. 1.0 nL 1.0 mL

The active compounds, GELRITE"1 gellan gum, phosphate buffer salts, benzyldodecinium bromide and Polysorbate 80 are added to and suspended or dissolved in water. The pH of the composition is adjusted to 5.5-6.0 and diluted to volume. The composition is rendered sterile by ionizing radiation. -41- LV 10388 EXAMPLE 30

II 2.0 ig 0.2 mg SOLUTION COMPOSITION R-(+)-3,4-Dihydro-2-(2-methoxy)-ethyl-4-propylamino-2H-thieno-[3,2-e]-l,2-thiazine-6-sulfon-amide l,l-dioxide hydrochloride- 10 (S)-(-)-1-( tert-butylami.no)-3-[(4-morpholino-l,2,5-thiadiazol-3-yl)oxy]-2-propanol maleate 0.5 mg 0.5 mg 15 20 GELRITE"1 gellan gum Monobasic sodium. phosphate . 2H20 Dibasic sodium phosphate •12H20 Benzyldodecinium bromide 6.0 mg 6.0 mg

Quantity sufficient to give final pH 5.5 - 6.0 0.10 mg 0.10 mg

Polysorbate. 80 0.2 mg 0.2 mg 25 Water for injection q.s. ad.

1,0 mL

1.0 mL

The active compounds, GELRITE™ gellan gum, phosphate buffer salts, benzyldodecinium bromide and Polysorbate 80 are added to and suspended or dissolved in water. The pH of the composition is adjusted to 5.5-6.0 and diluted to volume.

The composition is rendered sterile by ionizing radiation. 30 -42- EXAMPLE 31

SOLUTION COMPOSITION I II III (S,S)-(-)-5,6-dihydro-4-ethyl-amino-6-propyl-4H-thieno-[2,3b]thiopyran-2-sulfonamide- 7,7-dioxide monohydrochloride 22.26 g 22.26 g 1.113 g (S)-(-)-1-(tert-butvlamino)-3-[(4-morpholino-l,2,5-thiadiazol-3-yl)oxy]-2-propanol maleate 6.834 g 1.367 g 6.834 g Sodium citrate. 2^0 2.940 g 2.940 g 2.940 g Benzalkonium Chloride 0.075 g 0.075 g 0.075 g Hydroxyethylcellulose 5.00 g 5.00 g 5.00 g Sodium hydroxide q.s. pH = 6.0 pH = 6.0 pH = 6.0 Mannitol 16.00 g 21.00 g 35.90 g Water for injection q.s. ad. 1000 g 1000 g 1000 g

The active compounds, sodium citrate, benzalkonium chloride (in a 50Χ W/W solution), and mannitol are dissolved in approximately 400 mL water for injection in a tared and sterile vessel. The pH of the composition is adjusted to 6.0 by addition of 0.2 N sodium hydroxide solution, and water for injection is added until the weight of composition -43- LV 10388 equals 750 g. The composition is sterilized by filtration, pushing the solution with a 2 bar pressure of 0.45 micron filtrated nitrogen. Then 250 g of a 27. hydroxyethylcellulose autoclaved solution is added and the obtained solution is homogenized by stirring with a magnetic stirring bar. The solution is aseptically subdivided into 3.5 mL aliquots and sealed. EXAMPLE 32

SOLUTION COMPOSITION

I

II (S,S)-(-)-5,6-dihydro-4-ethyl-amino-6-propyl-4H-thieno- 2.0 mg 0.2 mg 0.5 mg 0.5 mg [2,3b]thiopyran-2-sulfonamide-7,7-dioxide monohydrochloride (S)-(-)-l-(iL£rt.-butylamino)-3-[(4-morpholino-l,2,5-thiadiazol-3-yl)oxy]-2-propanol maleate GELRITE™ gellan gum 6.0 mg 6.0 mg

Quantity sufficient to give final pH 5.5 - 6.0 0.10 mg 0.10 mg

Monobasic sodium phosphate .2H20

Dibasic sodium phosphate .12H20

Benzyldodecinium bromide

Polysorbate 80 0.2 mg 0.2 mg 5 -44-

Water for injection q.s. ad. 1.0 mL 1.0 mL

The active compounds, GELRITE™ gellan gum, phosphate buffer salts, benzyldodecinium bromide and Polysorbate 80 are added to and suspended or dissolved in water. The pH of the composition is adjusted to"5.5-6.0 and diluted to volume. The composition is rendered sterile by ionizing radiation. 10 EXAMPLE 33

Study of (S,S)-(-)-5,6-dihydro-4-ethylamino-6-methyl-4H-thieno[2,3b]thiopyran-2-sulfonamide-7,7-dioxide 15 (I) in combination with Timolol

Patients aged 40 or over, with either ocular hypertension or primary open angle glaucoma with an intraocular pressure (IOP) in one or both eyes of 22 20 mmHg or more at one time point each day while receiving timolol 0.57. twice a day (bid) alone were admitted to.the study. Patients had been on timolol 0.57. bid, either alone or in combination for at least three weeks prior to study entry and had been on 25 timolol 0.5% bid as their sole glaucoma therapy for at least two weeks prior to study admission.

Secondary glaucoma was an exclusion as was a history of glaucoma surgery or laser trabeculoplasty/gonioplasty. Patients for whom 30 timolol was contraindicated by the datasheet were excluded and also excluded were those on a concurrent 5 -45- β-blocker, carbonic anhydrase inhibitor, or clonidiņe. Thirty-one patients entered the study.

Procedure 1. Ali patients had their visual fields plotted by Goldmann Perimetry prior to study entry. 10 2. Patients were admitted for a 12 hour diurnal curve (i.e., IOP recorded at 08.00, 09.00, 10.00, 12.00, 14.00, 16.00, 18.00, 20.00 hours approximately, the 08.00 recording was inunediately prior to instillation of the drops). Ali pressures were measured by the same observer using the same Goldmann applanation tonometer. 15 20 3. Following recording of the baseline Diurnal Curve on timolol 0.5% bid, ali of the patients were instructed to add 1 drop of a solution to each eye at 8:10 pm and 8:10 am, ten minūtes after adding timolol, for seven days. The solution given to 16 of the patients contained 27« Compound I; the solution given to the other 15 patients was a placebo solution. 4. On Day 2, the IOP of each patient was measured at 8 am and 9 am, and a 12 hour diurnal curve was recorded on Day 8. 25 preliminary IOP data follow: 30 -46-

ΜΕΑΝ ΙΟΡ PRESTUDY AND

PERCENT C5ANGE IN IOP ΟΝ DAY 8 FROM PRESTUDY 5 COMPOUND I PLUS TĪMOLOL GROUP TIMOLOL TIMOLOL PLUS TIME BASELINE COMPOUND I 8am 27.4 -16.8 % 9am 27.1 -21.0 7. 10 10ām 25.4 -18.9 7. noon 25.6 -17.3 7. 2pm 24.5 -18.6 7. 4pm 25.2 -17.0 7. 6pm 25.7 -18.2 7. 15 8pm 24.4 -13.2 7. PLACEBO PLUS TIMOLOL GROUP TIMOLOL TIMOLOL PLUS TIME BASELINE PLACEBO 20 8am 26.9 - 3.4 7. 9am 24.2 - 4.5 7. 10ām 23.3 - 1.7 7. noon 23.2 + 0.2 7. 2pm 21.6 + 0.1 7. 25 4pm 22.7 - 0.1 7. 6pm 23.1 - 3.7 7. 8pm 21.9 + 6.6 7. These data are represented graphically in Figurē 30 Overall, Compound I given every 12 hours demonstrated a clinically and statistically -47-

LV significant effect over the effect of timolol alone, ranging from 137o-2l7o based on worse eye analysis.

Claims (10)

LV 10388 IZGUDROJUMA FORMULA OFTALMISKI SASTĀVI, KURI SATUR KARBOANHIDRĀZES INHIBITORA UN β-ADRENERĢISKĀ ANTAGONISTA KOMBINĀCIJAS 1. Oftalmisks sastāvs paaugstināta acs spiediena ārstēšanai, kas atšķiras ar to, ka tas satur oftalmoloģiski pieņemamu nesēju, 0,5 līdz 5 svara % karboanhidrāzes inhibitora vai tā oftalmoloģiski pieņemamu sāli un 0,01 līdz 1,0 % β-adrenerģiskā antagonista vai tā oftalmoloģiski pieņemamu sāli.EN 10388 INVENTIVE FORMULA CONTAINS CONTAINING CARBOANHIDRAZ INHIBITOR AND β-ADRENGENIC ANTAGONISTIC COMBINATION 1. An ophthalmic composition for the treatment of elevated ocular pressure, comprising an ophthalmologically acceptable carrier, 0.5 to 5% by weight of carbonic anhydrase inhibitor or ophthalmologically acceptable salt and 0.01 to 1.0% β-adrenergic antagonist or its ophthalmologically acceptable salt. 2. Sastāvs pēc punkta 1, kur karboanhidrāzes inhibitora koncentrācija ir 0,5 līdz 3 % un β-adrenerģiskā antagonista koncentrācija ir 0,1 līdz 0,5 %.2. A composition according to claim 1, wherein the concentration of the carbonic anhydrase inhibitor is 0.5 to 3% and the concentration of the β-adrenergic antagonist is 0.1 to 0.5%. 3. Oftalmiskais sastāvs pēc punkta 1 vai punkta 2 paaustināta acs spiediena ārstēšanai, kas satur oftalmoloģiski pieņememu nesēju, 0,05 līdz 5 % karboanhidrāzes inhibitora ar struktūru3. An ophthalmic composition according to claim 1 or claim 2 for treating an ocular pressure comprising an ophthalmologically acceptable carrier, a 0.05 to 5% carbonic anhydrase inhibitor with a structure atsevišķos diastereomērus, atsevišķos enantiomērus vai to maisījumus vai to oftalmoloģiski pieņememu sāli, kur A ir ogleklis vai slāpeklis; Z ir-NHR vai -OR; R ir C-j .6 alkilgrupa ar taisnu vai sazarotu virkni: R1 ir (a) ūdeņradis, (b) Cļ.3 alkilgrupa vai (c) Cļ .4 aikoksi-C-ļ .4 alkilgrupa; un ir -SO2- vai -C(0)-; X 2 un 0,01 līdz 1 % β-adrenerģiskā antagonista, kas izvēlēts no betaksolola, bufenolola, karteolola, levobunolola, metipranolola un timolola, vai tā oftalmoloģiski pieņemamu sāli.individual diastereomers, individual enantiomers or mixtures thereof, or an ophthalmic acceptable salt thereof, wherein A is carbon or nitrogen; Z is -NHR or -OR; R is a straight or branched C-j6 alkyl group: R 1 is (a) hydrogen, (b) C 1-3 alkyl or (c) C 1-4 alkoxy-C 1-4 alkyl; and is -SO2- or -C (O) -; X 2 and 0.01 to 1% of an β-adrenergic antagonist selected from betaxolol, bufenolol, cartolol, levobunolol, metipranolol and timolol, or an ophthalmologically acceptable salt thereof. 4. Sastāvs pēc punkta 3, kur A ir ogleklis, Z ir -NHR un X ir -SO2-.4. A composition according to claim 3, wherein A is carbon, Z is -NHR and X is -SO2-. 5. Sastāvs pēc punkta 3 vai 4, kur R ir a) -CH2CH3, b) -CH2CH2CH3 vai c) -CH2CH(CH3)2 ; R1 ir a) ūdeņradis, b) *CH3, c) -CH2CH2CH3, d) -CH2CH2CH2OCH3 vai e) -CH2OCH2CH3.A composition according to claim 3 or 4, wherein R is a) -CH 2 CH 3, b) -CH 2 CH 2 CH 3 or c) -CH 2 CH (CH 3) 2; R1 is a) hydrogen, b) * CH3, c) -CH2CH2CH3, d) -CH2CH2CH2OCH3 or e) -CH2OCH2CH3. 6. Sastāvs pēc jebkura no iepriekšējiem punktiem, kur β-adrenerģiskais antagonists ir timolols vai tā oftalmoloģiski pieņemams sāls.A composition according to any one of the preceding claims, wherein the β-adrenergic antagonist is timolol or an ophthalmologically acceptable salt thereof. 7. Sastāvs pēc jebkura no punktiem 3 līdz 6, kur A ir ogleklis un kur R ir -CH2CH3 un R1 ir -CH3 , vai R ir -CH2CH2CH3 un R1 ir -CH2CH2CH2OCH3 , vai R ir -CH2CH3 un R1 ir -CH2CH2CH3, vai R ir -CH2CH2(CH3)2 UN R1 ir ūdeņradis, vai R ir -CH2CH3 un R"! ir - CH2OCH2CH3, un karboanhidrāzes inhibitora abiem oglekļa atomiem 4 un 6 ir tikai S stereoķīmiskā konfigurācija.A composition according to any one of claims 3 to 6, wherein A is carbon and wherein R is -CH 2 CH 3 and R 1 is -CH 3, or R is -CH 2 CH 2 CH 3 and R 1 is -CH 2 CH 2 CH 2 OCH 3, or R is -CH 2 CH 3 and R 1 is -CH 2 CH 2 CH 3, or R is -CH 2 CH 2 (CH 3) 2 AND R 1 is hydrogen, or R is -CH 2 CH 3 and R " is CH2OCH2CH3, and both carbon atoms 4 and 6 of the carbonic anhydrase inhibitor have only the stereochemical configuration of S. 8. Sastāvs pēc punkta 7, kur karboanhidrāzes inhibitora koncentrācija ir 0,7 vai 2,0 % un timolola koncentrācija ir 0,5 %.8. A composition according to claim 7, wherein the carbonic anhydrase inhibitor has a concentration of 0.7 or 2.0% and a timolol concentration of 0.5%. 9. Sastāvs pēc jebkura no iepriekšējiem punktiem, kas papildus satur 0,1 līdz 2 % gellana sveķu (gummigela).9. A composition according to any one of the preceding claims, further comprising 0.1 to 2% gelligel. 10. Sastāva, kas atbilst jebkuram no iepriekšējiem punktiem, pielietošana paaustināta acs spiediena ārstēšanas zāļu ražošanai.Use of a composition according to any one of the preceding claims for the manufacture of a medicament for the treatment of pressurized eye pressure.